The invention relates to new imidazotriazolopyrimidines, processes for preparing them, pharmaceutical compositions comprising such compounds, and their use as medicaments for the treatment of various disease conditions.
It is known that adenosine antagonists may have a therapeutically useful effect in the treatment of diseases or pathological conditions that are somehow caused by activation of adenosine receptors.
Adenosine is an endogenous modulator with predominantly inhibitory effects in the CNS, in the heart, in the kidneys and other organs. The effects of adenosine are mediated via at least three receptor sub-types: adenosine A1, A2 and A3 receptors. Adenosine A2 receptors are further subdivided into two subtypes, A2a and A2b. The two A2 receptor subtypes can be differentiated, e.g. because specific adenosine antagonists such as CGS 21680 stimulate predominantly only the A2a subtype. It is presumed that the A2b subtype has a relatively low affinity for adenosine. For this reason, relatively high concentrations of adenosine are necessary in order to stimulate this subtype. Such high concentrations would be expected, for example, in the epithelial surface fluid in the lungs of asthmatics or in ischaemic tissue damage.
In the CNS, adenosine develops inhibitory effects mainly by activating A1 receptors: presynaptically by inhibiting the synaptic transmission (inhibiting the release of neurotransmitters such as acetylcholine, dopamine, noradrenaline, serotonin, glutamate, etc.), and postsynaptically by inhibiting neuronal activity.
A1 antagonists cancel out the inhibitory effects of adenosine and promote neuronal transmission and neuronal activity.
A1 antagonists are therefore of great interest for treating degenerative diseases of the central nervous system such as senile dementia of the Alzheimer""s type and age-related disorders of memory and learning capacity.
The disease includes, in addition to forgetfulness in its mild form and total helplessness and absolute dependence on care in its severe form, a number of other accompanying symptoms such as sleep disorders, motor co-ordination disorders ranging up to Parkinson""s syndrome, in addition to increased emotional instability and depressive symptoms. The disease is progressive and can lead to death. The treatments used hitherto have been unsatisfactory. At present there are no specific therapeutic agents at all. Attempts at treatment with acetylcholinesterase inhibitors show an effect in only a small proportion of the patients, but involve a high level of side effects.
The pathophysiology of Alzheimer""s disease and SDAT is characterised by a severe deterioration of the cholinergic system, but other transmitter systems are also affected. As a result of the loss of presynaptic cholinergic and other neurones and the resulting lack of preparation of neurotransmitters the neuronal transmission and neuronal activity in the areas of the brain essential for learning and memory are significantly reduced.
Selective adenosine A1 receptor antagonists promote neuronal transmission by the increased production of neurotransmitters, increase the excitability of postsynaptic neurones and can therefore counteract the symptoms of the disease.
The high receptor affinity and selectivity of some of the compounds claimed ought to make it possible to treat Alzheimer""s disease and SDAT with low doses, so that hardly any side effects need be expected which cannot be put down to the blockade of A1 receptors.
Another indication for centrally-acting adenosine A1 antagonists is depression. The therapeutic success of antidepressant substances appears to be linked to the regulation of A1 receptors. A1 antagonists may lead to the regulation of adenosine A1 receptors and thus offer a new therapeutic approach to the treatment of depressive patients.
Other areas of use for A2 selective adenosine antagonists, in particular, are neurodegenerative diseases such as Parkinson""s disease and also migraine. Adenosine inhibits the release of dopamine from central synaptic endings by interacting with dopamine-D2 receptors. A2 antagonists increase the release and availability of dopamine and thus offer a new therapeutic approach to the treatment of Parkinson""s disease.
In migraine, the vasodilatation of cerebral blood vessels mediated by A2 receptors appears to be involved. Selective A2 antagonists inhibit the vasodilatation and can therefore be useful in treating migraine.
Adenosine antagonists may also be used for treating peripheral indications.
For example, the activation of A1, A2 or A3 receptors in the lung may lead to bronchoconstriction. Selective adenosine A1 antagonists relax the tracheal smooth muscle, cause bronchodilatation and can thus be useful as antiasthmatic agents.
Adenosine A2b or A3 receptors are located on mast cells. Their activation causes the release of mast cell products such as histamine, tryptase or interleukin 8. Adenosine A3 receptors are found on eosinophiles and the stimulation of these receptors can influence the activation, chemotaxis and apoptosis of eosinophiles. Therefore, antagonists of A2b or A3 receptors are very promising for the treatment of allergic diseases such as e.g. rhinitis, urticaria, pruritis, allergic dermatitis, allergic eye diseases and nasal polyps. In addition, the effect of adenosine A2b or A3 antagonists on mast cells and eosinophiles may also be helpful in the treatment of asthma.
Furthermore, the anti-mast cell activity may be useful for reducing reperfusion damage after cardiac ischaemia.
By activating A2 receptors, adenosine may cause, inter alia, respiratory depression and cessation of breathing. A2 antagonists bring about respiratory stimulation. For example, adenosine antagonists (theophyllin) are used to treat respiratory distress and prevent sudden infant death in premature babies.
Adenosine stimulates the production of mucus by epithelial cells. The activation of adenosine A2b receptors on bronchial epithelial cells stimulates the chloride transportation which affects the consistency of mucus. Consequently, adenosine antagonists offer new therapeutic approaches to the treatment of diseases in which the quantity or consistency of the mucus is pathological, as in bronchitis and chronic obstructive pulmonary diseases, for example.
Adenosine A2b receptors are also located on the epithelial cells of the intestine. In the intestinal cells, too, the activation of these receptors can lead to increased chloride transportation. It is suspected that during inflammations of the intestines adenosine is released by neutrophiles, for example. The effect of the released adenosine on the chloride transportation influences the motility and absorption capacity of the intestinal epithelium. As a result, adenosine antagonists are possible therapeutic agents for inflammatory intestinal diseases and diarrhoea.
Other important therapeutic fields for adenosine antagonists are cardiovascular diseases and kidney diseases.
In the heart, adenosine inhibits electrical and contractile activity by activating A1 receptors. Combined with coronary vasodilatation mediated via A2 receptors, adenosine has a negative chronotropic, inotropic, dromotropic, bathmotropic and bradycardiac effect and reduces the volume of the heart per minute.
Adenosine A1 receptor antagonists or adenosine A3 receptor antagonists can prevent the damage caused to the heart and brain or lungs by ischaemia and subsequent reperfusion. As a result, adenosine antagonists can be used for the prevention or early treatment of damage to the heart caused by ischaemia/reperfusion e.g. after coronary bypass surgery, heart transplants, angioplasty or thrombolytic therapy of the heart and similar interventions. Moreover, adenosine antagonists can be used for the early treatment of cerebral ischaemia. The same is true of the lungs.
On the kidneys, the activation of A1 receptors causes vasoconstriction of afferent arterioles and as a result a drop in renal bloodflow and glomerular filtration. A1 antagonists act on the kidneys as powerful potassium-saving diuretics and can thus be used to protect the kidneys and to treat oedema, renal insufficiency and acute kidney failure.
On account of the adenosine antagonism on the heart and the diuretic effect, A1 antagonists can be used to therapeutic effect in various cardiovascular diseases, e.g. in cardiac insufficiency, arrythmias (bradyarrythmias) associated with hypoxia or ischaemia, transmission disorders, hypertension, ascites in liver failure (hepato-renal syndrome) and as an analgesic in circulatory disorders.
Adenosine may stimulate or inhibit cell apoptosis, via the adenosine A3 receptors and depending on the type of cell and the concentration of the receptor ligand. This effect can be reversed by adenosine A3 receptor antagonists. Consequently, adenosine A3 receptor antagonists are possible therapeutic agents for diseases in which a disruption of apoptosis is involved, such as for example inflammatory diseases such as arthritis, autoimmune diseases such as lupus erythematodes disseminatus or scleroderma and cancer. Types of cancer which overexpress the adenosine receptor would be particularly suitable for treatment with adenosine A3 receptor antagonists. Moreover, adenosine A3 receptor antagonists may be used to promote the immunological protective mechanisms against any remaining malignant cancer cells (e.g. after surgical removal of a colon carcinoma or other types of tumour).
A3 antagonists inhibit the degranulation of mast cells caused by A3 receptor activation and are therefore therapeutically useful in all disease and pathological situations connected with mast cell degranulation: e.g. as anti-inflammatory substances, in hypersensitivity reactions such as e.g. asthma, allergic rhinitis, urticaria, in myocardiac reperfusion injury, scleroderma, arthritis, autoimmune diseases, inflammatory bowel diseases and the like.
Cystic fibrosisxe2x80x94also known as mucoviscidosisxe2x80x94is an inherited metabolic (a major metabolic) disorder caused by a genetic defect on a certain chromosome. As a result of increased production and greater viscosity of the secretions of the mucosal glands in the bronchi, it may lead to severe complications in the airways. Preliminary investigations have shown that A1 antagonists increase the efflux of chloride ions, e.g. in CF PAC cells. On the basis of these findings, it may be expected that, in patients suffering from cystic fibrosis (mucoviscidosis), the compounds according to the invention will regulate the disrupted electrolyte balance of the cells and alleviate the symptoms of the disease.
In its first aspect, the invention provides new imidazotriazolopyrimidine derivatives of the formula (I) 
wherein the dotted lines between the nitrogen atoms of the above general formula I indicate the existence of a double bond in one of two possible positions, so that the groups R4 and R6 and R3 and R2 need not be present simultaneously and wherein:
R1 denotes hydrogen, a C1-8-alkyl, C2-8-alkenyl or C2-8-alkynyl group which may optionally be mono- or polysubstituted by xe2x80x94CN, xe2x80x94CH2NR7R8, xe2x80x94COOR9, xe2x80x94CONR7R8, xe2x80x94CHO, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CHxe2x95x90NOH, xe2x80x94CHxe2x95x90NOR9, xe2x80x94NR7R8, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94NHCONHPhenyl, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R1 denotes xe2x80x94CHO, xe2x80x94COOR9, xe2x80x94CONR7R8 or NR7R8;
R1 denotes C3-7-cycloalkyl, preferably cyclopentyl or cyclohexyl, which may optionally be substituted by xe2x95x90O, xe2x80x94OR9, OCOR9 or xe2x80x94OCOPyridyl;
R1 denotes phenyl which may optionally be substituted by C14-alkyl, preferably methyl, xe2x80x94CN, xe2x80x94COOR9, NR7R8, xe2x80x94OR9, xe2x80x94OCH2COOR9, xe2x80x94OCH2CONR7R8, xe2x80x94SO3H or halogen;
R1 denotes phenyl-C1-6-alkyl, preferably phenyl-C1-4-alkyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring may optionally be substituted, either directly or via an alkylene bridge having 1 to 4 carbon atoms, by one or more of the groups C1-3-alkyl, xe2x80x94CN, xe2x80x94CH2OCOR9, xe2x80x94COOR9, xe2x80x94CF3, xe2x80x94CONR7R8, xe2x80x94CH2OR9, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR9, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94COxe2x80x94R9, xe2x80x94COxe2x80x94C1-4-alkylxe2x80x94NR7R8, NR7R8, xe2x80x94NO2, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, xe2x80x94OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R1 denotes C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl-C2-6-alkenyl, C3-7-cycloalkyl-C2-6-alkynyl, wherein the cycloalkyl group may optionally be substituted, either directly or via an alkylene bridge having 1 to 4 carbon atoms, by one or more of the groups C1-3-alkyl, xe2x80x94CN, xe2x80x94CH2OCOR9, xe2x80x94COOR9, xe2x80x94CF3, xe2x80x94CONR7R8, xe2x80x94CH2OR9, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR9, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CH2OCONR7R8, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94COxe2x80x94R9, xe2x80x94COxe2x80x94C1-4-Alkyl-NR7R8, NR7R8, xe2x80x94NO2, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, xe2x80x94OCONR7R8, halogen, optionally methyl-substituted 1,3-dioxolane or 1,3-dioxane;
R1 denotes a norbornane, norbornene, C3-6-dicycloalkyl-methyl, preferably dicyclopropylmethyl, adamantane or noradamantane group which may optionally be substituted by C1-4-alkyl, preferably methyl;
R1 denotes a group of formula Axe2x80x94C1-6-alkyl, Axe2x80x94CONHxe2x80x94C1-6-alkyl, Axe2x80x94CONHxe2x80x94C2-6-alkenyl, Axe2x80x94CONHxe2x80x94C2-6-alkynyl, Axe2x80x94NHxe2x80x94COxe2x80x94C1-6-alkyl, Axe2x80x94NHxe2x80x94COxe2x80x94C2-6-alkenyl, Axe2x80x94NHxe2x80x94COxe2x80x94C2-6-alkynyl, Axe2x80x94C2-6-alkenyl, Axe2x80x94C2-6-alkynyl or Axe2x80x94, where A is a C- or N-linked 5-, 6- or 7-membered heterocycle, which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally methoxy-substituted benzyl, C1-4-alkyl, xe2x80x94CN, xe2x80x94CH2NR7R8, xe2x80x94COOR9, xe2x80x94CONR7R8, xe2x80x94COR10, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OR9, xe2x95x90O, a ketal, ethyleneketal, xe2x80x94SO3H, xe2x80x94SO2xe2x80x94R9 or halogen;
R2 or R3 denotes a C1-8-alkyl, C2-8-alkenyl or C2-8-alkynyl group which may optionally be mono- or polysubstituted by xe2x80x94CN, xe2x80x94CH2NR7R8, xe2x80x94COOR9, xe2x80x94CONR7R8, xe2x80x94CHO, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CHxe2x95x90NOH, xe2x80x94CHxe2x95x90NOR9, xe2x80x94NR7R8, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94NHCONHPhenyl, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R2 or R3 denotes phenyl-C1-6-alkyl, preferably phenyl-C1-4-alkyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring may optionally be substituted, either directly or via an alkylene bridge having 1 to 4 carbon atoms, by one or more of the groups C1-3-alkyl, xe2x80x94CN, xe2x80x94CH2OCOR9, xe2x80x94COOR9, xe2x80x94CF3, xe2x80x94CONR7R8, xe2x80x94CH2OR9, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR9, xe2x80x94COR10, xe2x80x94CH(OH)R10, CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94COxe2x80x94R9, xe2x80x94COxe2x80x94C1-4-alkyl-NR7R8, NR7R8, xe2x80x94NO2, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, xe2x80x94OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R2 or R3 denotes a group of formula Axe2x80x94C1-6-alkyl, Axe2x80x94CONHxe2x80x94C1-6-alkyl, Axe2x80x94CONHxe2x80x94C2-6-alkenyl, Axe2x80x94CONHxe2x80x94C2-6-alkynyl, Axe2x80x94NHxe2x80x94COxe2x80x94C1-6-alkyl, Axe2x80x94NHxe2x80x94COxe2x80x94C2-6-alkenyl, Axe2x80x94NHxe2x80x94COxe2x80x94C2-6-alkynyl, Axe2x80x94C2-6-alkenyl, Axe2x80x94C2-6-alkynyl or Axe2x80x94, where A is a C- or N-linked 5-, 6- or 7-membered heterocycle, which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally methoxy-substituted benzyl, C1-4-alkyl, xe2x80x94CN, xe2x80x94CH2NR7R8, xe2x80x94COOR9, xe2x80x94CONR7R8, xe2x80x94COR10, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OR9, xe2x95x90O, a ketal, ethyleneketal, xe2x80x94SO3H, xe2x80x94SO2xe2x80x94R9 or halogen;
R4 or R5 denotes hydrogen, C1-4-alkyl which may optionally be substituted by xe2x80x94NR7R8, benzyl, but preferably hydrogen;
R5 denotes hydrogen, a C1-8-alkyl, C2-8-alkenyl or C2-8-alkynyl group which may optionally be mono- or polysubstituted by xe2x80x94CN, xe2x80x94CH2NR7R8, COOR9, xe2x80x94CONR7R8, xe2x80x94CHO, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CHxe2x95x90NOH, xe2x80x94CHxe2x95x90NOR9, xe2x80x94NR7R8, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94NHCONHPhenyl, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R5 denotes C3-7-cycloalkyl, preferably cyclopentyl or cyclohexyl, which may optionally be substituted by xe2x95x90O, xe2x80x94OH, xe2x80x94OR9, OCOR9 or xe2x80x94OCOPyridyl;
R5 denotes phenyl which may optionally be substituted by xe2x80x94OH, halogen, xe2x80x94OR9, C1-4-alkyl, preferably xe2x80x94CH3, xe2x80x94NH2, xe2x80x94COOH, xe2x80x94SO3H, xe2x80x94COOR9, xe2x80x94OCH2COOR9, xe2x80x94CN or xe2x80x94OCH2CONR7R8;
R5 denotes phenyl-C1-6-alkyl, preferably phenyl-C1-4-alkyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring may optionally be substituted, either directly or via an alkylene bridge having 1 to 4 carbon atoms, by one or more of the groups C1-3-alkyl, xe2x80x94CN, xe2x80x94CH2OCOR9, xe2x80x94COOR9, xe2x80x94CF3, xe2x80x94CONR7R8, xe2x80x94CH2OR9, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR9, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94COxe2x80x94R9, xe2x80x94COxe2x80x94C1-4-alkyl-NR7R8, NR7R8, xe2x80x94NO2, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, xe2x80x94OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R5 denotes a norbornane, norbornene, C3-6-dicycloalkyl-methyl, preferably dicyclopropylmethyl, adamantane or noradamantane group which may optionally be substituted by C1-4-alkyl, preferably methyl;
R5 denotes xe2x80x94CHO, xe2x80x94COOR9, xe2x80x94CONR7R8 or NR7R8;
R5 denotes C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl-C2-6-alkenyl, C3-7-cycloalkyl-C2-6-alkynyl, wherein the cycloalkyl group may optionally be substituted, either directly or via an alkylene bridge having 1 to 4 carbon atoms, by one or more of the groups C1-3-alkyl, xe2x80x94CN, xe2x80x94CH2OCOR9, xe2x80x94COOR9, xe2x80x94CF3, xe2x80x94CONR7R8, xe2x80x94CH2OR9, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR9, xe2x80x94COR10, xe2x80x94CH(OH)R10, xe2x80x94CH(OR9)2, xe2x80x94CHxe2x95x90CHxe2x80x94R11, xe2x80x94CH2xe2x80x94OCONR7R8, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CONR7R8, xe2x80x94COxe2x80x94R9, xe2x80x94COxe2x80x94C1-4-Alkylxe2x80x94NR7R8, NR7R8, xe2x80x94NO2, xe2x80x94NHCOR9, xe2x80x94NHCONR7R8, xe2x80x94NHCOOR9, xe2x80x94OR9, xe2x80x94OCOR9, xe2x80x94OCOPyridyl, xe2x80x94OCH2COOR9, xe2x80x94OCH2xe2x80x94CONR7R8, xe2x80x94OCH2xe2x80x94CH2xe2x80x94NR7R8, xe2x80x94OCH2CH2OR9, xe2x80x94OCH2xe2x80x94CH2OCOR9, xe2x80x94OCONR7R8, halogen, 1,3-dioxane or optionally methyl-substituted 1,3-dioxolane;
R5 denotes a group of formula Axe2x80x94C1-6-alkyl, Axe2x80x94CONHxe2x80x94C1-6-alkyl, Axe2x80x94CONHxe2x80x94C2-6-alkenyl, Axe2x80x94CONHxe2x80x94C2-6-alkynyl, Axe2x80x94NHxe2x80x94COxe2x80x94C1-6-alkyl, Axe2x80x94NHxe2x80x94COxe2x80x94C2-6-alkenyl, Axe2x80x94NHxe2x80x94COxe2x80x94C2-6-alkynyl, Axe2x80x94C2-6-alkenylene, Axe2x80x94C2-6-alkynylene or Axe2x80x94, where A is a C- or N-linked 5-, 6- or 7-membered heterocycle, which contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally methoxy-substituted benzyl, C1-4-alkyl, xe2x80x94CN, xe2x80x94CH2NR7R8, xe2x80x94COOR9, xe2x80x94CONR7R8, xe2x80x94COR10, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OR9, xe2x95x90O, a ketal, ethyleneketal, xe2x80x94SO3H, xe2x80x94SO2xe2x80x94R9 or halogen;
R7 denotes hydrogen, C1-8-alkyl, preferably C1-4-alkyl, which may optionally be substituted by xe2x80x94COOR9, xe2x80x94COR10, xe2x80x94OR9, OCOR9, amino, phenyl, methoxy-substituted phenyl or amino, or a C3-6-cycloalkyl;
R7 denotes a 5-, 6- or 7-membered heterocycle C-linked directly or via a C1-4-alkyl chain, which contains one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and which is optionally mono- or polysubstituted, preferably monosubstituted, by benzyl, methoxy-substituted benzyl, C1-4-alkyl, halogen, xe2x80x94OR9, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x95x90O, xe2x80x94SO3H or xe2x80x94COOR9;
R8 denotes hydrogen, C1-8-alkyl, preferably C1-4-alkyl, which may optionally be substituted by xe2x80x94COOR9, xe2x80x94COR10, xe2x80x94OR9, OCOR9, amino, phenyl, methoxy-substituted phenyl or amino, or a C3-6-cycloalkyl, or
R8 denotes a 5-, 6- or 7-membered heterocycle C-linked directly or via a C1-4-alkyl chain, which contains one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and which is optionally mono- or polysubstituted, preferably monosubstituted, by benzyl, methoxy-substituted benzyl, C1-4-alkyl, halogen, xe2x80x94OR9, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x95x90O, xe2x80x94SO3H or xe2x80x94COOR9; or
R7 and R8 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain nitrogen, oxygen or sulphur as further heteroatoms, whilst the heterocycle may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, or may carry one of the groups xe2x80x94CN, xe2x80x94COOR9, xe2x80x94CONH2, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OR9, xe2x80x94SO3H, xe2x80x94SO2xe2x80x94R9, halogen or xe2x80x94(CH2)n-phenyl, xe2x80x94(CH2)nxe2x80x94NH2, xe2x95x90O, xe2x80x94OCH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94OCH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94C1-4-alkyl, xe2x80x94(CH2)nxe2x80x94N(C1-4-alkyl)2, xe2x80x94(CH2)nxe2x80x94NHCOOR9, wherein n=1, 2, 3 or 4;
R9 denotes hydrogen, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, a benzyl or phenyl group which may optionally be mono- or polysubstituted by xe2x80x94OCH3;
R10 denotes C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, optionally methoxy-substituted phenyl, optionally methoxy-substituted benzyl, C3-6-cycloalkyl;
R11 denotes hydrogen, C1-3-alkyl, xe2x80x94COOR9, xe2x80x94CH2OR9, xe2x80x94CH2NR7R8, xe2x80x94CONR7R8 or optionally methoxy-substituted phenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
These are adenosine antagonists and are useful for, inter alia, the treatment of senile dementia of the Alzheimer""s type.
Preferred compounds of general formula (I) are those wherein
R1 denotes hydrogen, C1-8-alkyl which may optionally be substituted by xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COO-phenyl, xe2x80x94COO-benzyl, xe2x80x94CONR7R8, xe2x80x94COxe2x80x94C1-4-alkyl-NR7R8, xe2x80x94COxe2x80x94C1-4-alkyl, xe2x80x94CHO, xe2x80x94NR7R8, xe2x95x90NOH, xe2x80x94NHCOxe2x80x94C1-4-alkyl, xe2x80x94NHCO-phenyl, hydroxy, xe2x95x90O, C1-4-alkoxy, phenyloxy, xe2x80x94O-phenyl-C1-4-alkyloxy, benzyloxy, xe2x80x94O-benzylxe2x80x94Oxe2x80x94C1-4-alkyloxy, xe2x80x94OCOxe2x80x94C1-4-alkyl, xe2x80x94OCO-phenyl, xe2x80x94OCO-benzyl, xe2x80x94OCO-pyridyl, xe2x80x94Oxe2x80x94C2-4-alkylene or halogen;
R1 denotes xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COO-phenyl, xe2x80x94COO-benzyl, xe2x80x94CONR7R8 or an amine of general formula NR7R8;
R1 denotes phenyl which may optionally be substituted by C1-4-alkyl, -COxe2x80x94C14-alkyl, C1-4-alkyl-NR7R8, C1-4-alkyl-OH, C1-4-alkylxe2x95x90NOH, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COOxe2x80x94phenyl, xe2x80x94COO-benzyl, xe2x80x94CONR7R8, xe2x80x94COxe2x80x94C1-4-alkylxe2x80x94NH2, NR7R8, hydroxy, C1-4-alkyloxy, benzyloxy, phenyloxy, xe2x80x94OCOxe2x80x94C1-4-alkyl, xe2x80x94OCO-phenyl, xe2x80x94OCO-benzyl, xe2x80x94OCO-pyridyl, xe2x80x94Oxe2x80x94C2-4-alkenyl or halogen, preferably chlorine or fluorine;
R1 denotes a C3-6-cycloalkyl or C3-6-cycloalkyl-C1-4-alkyl group which may optionally be substituted by xe2x95x90O, hydroxy, C1-4-alkyl or C1-4-alkyloxy;
R1 denotes a norbornane, norbornene, adamantane or noradamantane group which may optionally be substituted by C1-4-alkyl, preferably methyl;
R1 denotes phenyl-C1-4-alkyl, preferably benzyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring may optionally be substituted by C1-4-alkyl, xe2x80x94COxe2x80x94C1-4-alkyl, C1-4-alkyl-NR7R8, C1-4-alkyl-OH, C1-4-alkylxe2x95x90NOH, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COO-phenyl, xe2x80x94COO-benzyl, xe2x80x94CONR7R8, xe2x80x94COxe2x80x94C1-4-alkyl-NH2, NR7R8, hydroxy, C1-4-alkyloxy, benzyloxy, phenyloxy, xe2x80x94OCOxe2x80x94C1-4-alkyl, xe2x80x94OCO-phenyl, xe2x80x94OCO-benzyl, xe2x80x94OCO-pyridyl, xe2x80x94Oxe2x80x94C2-4-alkylene or halogen, preferably chlorine or fluorine;
R1 denotes a 5- or 6-membered heterocycle optionally C- or N-linked either directly or via an alkylene bridge having 1 to 4 carbon atoms, which contains one, two or three heteroatoms selected from the group comprising nitrogen or oxygen and which is optionally mono- or polysubstituted by benzyl or C1-4-alkyl;
R2 or R3 denotes a C1-8-alkyl which may optionally be substituted by xe2x80x94NR7R8, OH or COOH; or
R2 or R3 denotes C2-8-alkenyl, phenyl-C1-4-alkyl, preferably benzyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, whilst the phenyl ring may optionally be substituted by hydroxy, C1-4-alkyl, C1-4-alkyloxy, xe2x80x94NR7R8or halogen, preferably chlorine or fluorine;
R2 or R3 denotes a 5- or 6-membered heterocycle optionally C- or N-linked either directly or via an alkylene bridge having 1 to 4 carbon atoms, which contains one, two or three heteroatoms selected from the group comprising nitrogen or oxygen and which is optionally mono- or polysubstituted by benzyl or C1-4-alkyl;
R4 or R6 denotes hydrogen, C1-4-alkyl which may optionally be substituted by xe2x80x94NR7R8, or benzyl;
R5 denotes hydrogen, C1-8-alkyl, preferably C1-6-alkyl;
R5 denotes phenyl which may optionally be substituted by C1-4-alkyl, C1-4-alkyloxy, hydroxy, xe2x80x94NR7R8 or halogen, preferably chlorine or fluorine;
R5 denotes phenyl-C1-6-alkyl, preferably benzyl, whilst the phenyl ring may optionally be substituted by C1-4-alkyl, C1-4-alkyloxy, hydroxy, xe2x80x94NR7R8 or halogen, preferably chlorine or fluorine;
R5 denotes an optionally substituted amine, preferably xe2x80x94NR7R8;
R5 denotes a 5- or 6-membered heterocycle optionally C- or N-linked either directly or via a C1-4-alkylene bridge, which contains one or more heteroatoms selected from the group comprising nitrogen or oxygen and which is optionally substituted by benzyl or C1-4-alkyl;
R5 denotes a C3-6-cycloalkyl which may optionally be substituted by xe2x95x90O, hydroxy, C1-4-alkyl or C1-4-alkyloxy;
R5 denotes a norbornane, norbornene, adamantane or noradamantane group which may optionally be substituted by C1-4-alkyl, preferably methyl;
R7 denotes hydrogen, a branched or unbranched C1-4-alkyl group;
R7 denotes a C-linked 5- or 6-membered heterocycle which contains one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and which is optionally substituted by benzyl, C1-4-alkyl, C1-4-alkyloxy, halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH or xe2x95x90O;
R8 denotes hydrogen, a branched or unbranched C1-4-alkyl group;
R8 denotes a C-linked 5- or 6-membered heterocycle which contains one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and which is optionally substituted by benzyl, C1-4-alkyl, C1-4-alkyloxy, halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH or xe2x95x90O; or
R7 and R8 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain nitrogen or oxygen as further heteroatoms, whilst the heterocycle may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, or by a xe2x80x94(CH2)1-4-phenyl group, preferably benzyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Also preferred are the compounds of general formula (I) wherein
R1 denotes hydrogen, C1-6-alkyl, preferably C1-4-alkyl, which may optionally be substituted by xe2x80x94COxe2x80x94C1-4-alkyl, xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COO-phenyl, xe2x80x94COO-benzyl, xe2x80x94CONR7R8, xe2x80x94COxe2x80x94C1-4-alkyl-NR7R8, xe2x80x94NR7R8, xe2x80x94NHCOxe2x80x94C1-4-alkyl, xe2x80x94NHCO-Phenyl, hydroxy, xe2x95x90O, C1-4-alkoxy, phenyloxy, xe2x80x94O-phenylxe2x80x94Oxe2x80x94C1-4-alkyloxy, benzyloxy, xe2x80x94O-benzylxe2x80x94Oxe2x80x94C1-4-alkyloxy, xe2x80x94OCOxe2x80x94C1-4-alkyl, xe2x80x94OCO-phenyl, xe2x80x94OCO-pyridyl, xe2x80x94OCO-benzyl, xe2x80x94Oxe2x80x94C2-4-alkylene or halogen;
R1 denotes phenyl, whilst the phenyl ring may optionally be substituted by C1-4-alkyl, hydroxy, C1-4-alkyloxy, NR7R8, halogen, preferably fluorine or chlorine;
R1 denotes phenyl-C1-3-alkyl, preferably benzyl, whilst the phenyl ring may optionally be substituted by C1-4-alkyl, xe2x80x94COxe2x80x94C1-4-alkyl, xe2x80x94C1-4-alkyl-NR7R8, xe2x80x94C1-4-alkylxe2x80x94OH, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COO-phenyl, xe2x80x94COO-benzyl, xe2x80x94CONR7R8, xe2x80x94COxe2x80x94C1-4-alkyl-NR7R8, NR7R8, hydroxy, C1-4-alkyloxy, benzyloxy, phenyloxy, xe2x80x94OCOxe2x80x94C1-4-alkyl, xe2x80x94OCO-phenyl, xe2x80x94OCO-benzyl, xe2x80x94OCO-pyridyl, xe2x80x94Oxe2x80x94C2-4-alkylene or halogen, preferably fluorine or chlorine;
R1 denotes a cyclopentyl, cyclohexyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydroxycyclohexane linked via a single bond or via an alkylene chain having 1 to 4 carbon atoms;
R1 denotes xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl, xe2x80x94COO-phenyl, xe2x80x94COO-benzyl, xe2x80x94COxe2x80x94NHxe2x80x94C1-4-alkyl, xe2x80x94COxe2x80x94N(C1-4-alkyl)2 or xe2x80x94COxe2x80x94NH-phenyl;
R1 denotes an amine of general formula NR7R8;
R1 denotes a heterocycle selected from the group consisting of furan, tetrahydrofuran, xcex1-pyran, xcex3-pyran, dioxolane, tetrahydropyran, dioxane, thiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, morpholine, thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole and pyrazolidine linked via a single bond or via an alkylene chain with 1 to 4 carbon atoms;
R2 or R3 denotes C1-7-alkyl, preferably C1-5-alkyl, which may optionally be substituted by xe2x80x94NR7R8, OH or COOH; or
R2 or R3 denotes C2-5-alkenyl or phenyl-C1-3-alkyl, preferably benzyl, whilst the phenyl ring may be substituted by C1-4-alkyl, xe2x80x94NR7R8, hydroxy, C1-4-alkyloxy or halogen, preferably chlorine or fluorine;
R2 or R3 denotes a heterocycle selected from the group consisting of furan, tetrahydrofuran, xcex1-pyran, xcex3-pyran, dioxolane, tetrahydropyran, dioxane, thiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, morpholine, thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole and pyrazolidine linked via a single bond or via an alkylene chain with 1 to 4 carbon atoms;
R4 or R6 denotes hydrogen, C1-4-alkyl, preferably C1-3-alkyl, C1-3-alkyl-NR7R8 or benzyl;
R5 denotes hydrogen, C1-6-alkyl, preferably C1-4-alkyl;
R5 denotes cyclopentyl, cyclohexyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydroxycyclohexane;
R5 denotes pyridyl, tetrahydrofuranyl, tetrahydropyranyl, furyl, morpholine, piperidine or piperazine which is optionally substituted by C1-4-alkyl or benzyl;
R5 denotes a phenyl group which may optionally be substituted by C1-4-alkyl, halogen or hydroxy;
R5 denotes phenyl-C1-4-alkyl, preferably benzyl, whilst the phenyl ring may optionally be substituted by C1-4-alkyl, xe2x80x94NR7R8, hydroxy, C1-4-alkyloxy or halogen, preferably fluorine or chlorine;
R5 denotes an amine of general formula xe2x80x94NR7R8;
R5 denotes a norbornene, norbornane, adamantane or noradamantane group which may optionally be substituted by C1-4-alkyl, preferably methyl;
R7 denotes hydrogen, a branched or unbranched C1-4-alkyl group;
R7 denotes a C-linked heterocycle selected from the group consisting of pyrrole, pyrrolidine, pyrazole, imidazole, imidazolidine, triazole, pyridine, piperidine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, thiazole, isothiazole and thiadiazole which is optionally substituted by C1-4-alkyl, xe2x80x94NO2, xe2x80x94NH2, hydroxy, C1-4-alkyloxy, chlorine or bromine;
R8 denotes hydrogen, a branched or unbranched C1-4-alkyl group, or
R denotes a C-linked heterocycle selected from the group consisiting of pyrrole, pyrrolidine, pyrazole, imidazole, imidazolidine, triazole, pyridine, piperidine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, thiazole, isothiazole and thiadiazole which is optionally substituted by C1-4-alkyl, xe2x80x94NO2, xe2x80x94NH2, hydroxy, C1-4-alkyloxy, chlorine or bromine; or
R7 and R8 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain nitrogen or oxygen as further heteroatoms, whilst the heterocycle may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, or by a xe2x80x94(CH2)1-4-phenyl group, preferably benzyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Preferred compounds according to the invention are compounds of general formula (I) wherein
R1 denotes hydrogen, or C1-4-alkyl, which is optionally substituted by xe2x80x94NHCOxe2x80x94C1-4-alkyl, xe2x80x94NR7R8, hydroxy, C1-4-alkyloxy, chlorine or bromine; or
R1 denotes xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-4-alkyl or phenyl; or
R1 denotes phenyl-C1-3-alkyl, preferably benzyl which may optionally be substituted by C1-4-alkyl, C1-4-alkyl-NR7R8, hydroxy, benzyloxy or fluorine; or
R1 denotes phenyloxy-C1-3-alkyl, preferably phenyloxymethyl, which may optionally be substituted by methoxy; or
R1 denotes benzyloxy-C1-3-alkyl, preferably benzyloxymethyl which may optionally be substituted by methoxy; or
R1 denotes benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxymethyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolylmethyl, N-morpholinomethyl, cyclopentyl or furyl;
R2 or R3 denote C1-5-alkyl, C2-4-alkenyl or benzyl;
R4 or R6 denote hydrogen, C1-3-alkyl, C1-3-alkylxe2x80x94NR7R8, N-morpholinoethyl or benzyl;
R5 denotes hydrogen, C1-4-alkyl, phenyl or benzyl wherein the phenyl ring may optionally be substituted by fluorine; or
R5 denotes pyridyl, piperidinyl, morpholinyl, piperazinyl, 4-benzylpiperazinyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, NR7R8, cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornyl or norbornenyl;
R7 denotes hydrogen, C1-4-alkyl or pyridyl;
R8 denotes hydrogen, C1-4-alkyl or pyridyl
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Also preferred according to the invention are compounds of general formula (I) wherein
R1 denotes hydrogen, methyl, which may optionally be substituted by xe2x80x94NH2, xe2x80x94NHMe, xe2x80x94NMe2, xe2x80x94N(propyl)2, xe2x80x94NHAcetyl, hydroxy, methoxy, ethoxy, phenyloxy, methoxyphenyloxy, methoxybenzyloxy, piperazine, methylpiperazine, morpholine, benzoyloxy, pyridylcarbonyloxy, pyridine, pyridylamino, pyrrole or bromine; or
R1 denotes ethyl which is optionally substituted by xe2x80x94NH2 or hydroxy; or
R1 denotes benzyl which is optionally substituted by hydroxy, methoxy, benzyloxy, dimethylaminoethoxy, N-morpholinoethoxy or fluorine; or
R1 denotes n-propyl, isopropyl, n-butyl, tert.butyl, cyclopentyl, cyclohexylmethyl, phenyl, phenylethyl, xe2x80x94CHO, xe2x80x94COOH, xe2x80x94COOMe, COOEt, COOPropyl, COOButyl or furan;
R2 or R3 denote methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, allyl, butenyl, n-pentyl, propargyl or benzyl;
R4 or R6 denote hydrogen, methyl, n-propyl or benzyl; or
R4 or R5 denote ethyl which is optionally substituted by morpholine;
R5 denotes hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, phenyl, benzyl, pyridyl, xe2x80x94NH2, xe2x80x94NHMe, xe2x80x94NMe2, piperidinyl, morpholinyl; or
R5 denotes piperazinyl which is optionally substituted by methyl or benzyl; or
R5 denotes furyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornanyl or norbornenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred according to the invention are compounds of general formula (I) wherein
R1 denotes hydrogen, methyl which is optionally substituted by xe2x80x94NMe2, hydroxy, methoxy, ethoxy, phenyloxy, methoxyphenyloxy, methoxybenzyloxy, morpholine, benzoyloxy, pyridylcarbonyloxy, pyridine, pyridylamino or pyrrole; or
R1 denotes ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, cyclopentyl, cyclohexylmetyl or benzyl which is optionally be substituted by hydroxy, methoxy, dimethylaminoethoxy or fluorine;
phenyl, phenylethyl, xe2x80x94COOH, xe2x80x94COOMe or furan;
R2 or R3 denote methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl, allyl, butenyl, propargyl or benzyl;
R4 or R6 denote hydrogen;
R1 denotes hydrogen, ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, phenyl, benzyl, pyridine, piperidine, morpholine, piperazine, 4-benzylpiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, xe2x80x94NMe2, cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornanyl or 5-norbornenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Especially preferred according to the invention are compounds of general formula (I) wherein
R1 denotes methyl, which s optionally substituted by xe2x80x94NH2, xe2x80x94NHMe, xe2x80x94N(iso-propyl)2, -NHAcetyl, hydroxy, phenyloxy, methylpiperazine or pyrrole; or
R1 denotes ethyl which is optionally substituted by xe2x80x94NH2 or hydroxy; or
R1 denotes benzyl which is optionally substituted by hydroxy, methoxy, benzyloxy, dimethylaminoethoxy, N-morpholinoethoxy or fluorine; or
R1 denotes cyclopentyl phenylethyl, xe2x80x94COOH, xe2x80x94COOPropyl, xe2x80x94COOButyl or furan;
R2 or R3 denote ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, allyl, butenyl or propargyl;
R4 or R6 denote hydrogen, methyl or ethyl, which is substituted by morpholine;
R5 denotes methyl, ethyl, n-propyl, tert.butyl, cyclopentyl or norbornenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are also compounds of general formula (I) wherein
R1 denotes methyl, which is optionally substituted by phenyloxy or pyrrole; or
R1 denotes benzyl which is optionally substituted by hydroxy, methoxy, dimethylaminoethoxy or fluorine; or
R1 denotes cyclopentyl, furan or phenylethyl;
R2 or R3 denote ethyl, n-propyl, allyl or propargyl;
R4 or R1 denote hydrogen;
R5 denotes methyl, n-propyl, tert.butyl, cyclopentyl or norbornenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
The compounds of general formula (I) form the following isomers: 
the isomers of general formulae (Ia) and (Ib) being particularly preferred, especially those wherein R4 or R6 are hydrogen or C1-4-alkyl. Particularly preferred are compounds of general formula (Ia) and (Ib) wherein R4 and R6 denote hydrogenxe2x80x94in this case the isomers (Ia) and (Ib) are tautomers. According to the invention, the particularly preferred compounds are the isomers (Ia), especially those which have a I substituent in positions 2, 4 and 7.
If desired, the compounds of general formula (I) may be converted into their salts, more particularly, for pharmaceutical use, into their physiologically acceptable salts with an inorganic or organic acid. Suitable acids include for example succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid or citric acid. Mixtures of the abovementioned acids may also be used.
Suitable alkyl groups (including those which are components of other groups) are branched and unbranched alkyl groups having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl, hexyl, heptyl and octyl. In some cases the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. are used for the abovementioned groups.
Suitable alkenyl groups (including those which are components of other groups) are branched and unbranched alkenyl groups having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, provided that they have at least one double bond, as well as the abovementioned alkyl groups, for example, provided that they have at least one double bond, such as vinyl (provided that no unstable enamines or enolethers are formed), propenyl, isopropenyl, butenyl, pentenyl and hexenyl.
Suitable alkynyl groups (including those which are components of other groups) are alkynyl groups having 2 to 8 carbon atoms, provided that they have at least one triple bond, such as ethynyl, propargyl, butynyl, pentynyl and hexynyl.
Suitable cycloalkyl groups having 3 to 6 carbon atoms include, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which may also be substituted by branched or unbranched alkyl having 1 to 4 carbon atoms, hydroxy, and/or halogen or as hereinbefore defined. Halogen generally denotes fluorine, chlorine, bromine or iodine.
Examples of N-linked cyclic groups of general formula NR7R8 include: pyrrole, pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, preferably morpholine, piperazine and piperidine, whilst the abovementioned heterocycles may also be substituted by benzyl, alkyl having 1 to 4 carbon atoms, preferably methyl, or can be substituted as specified in the definitions.
Examples of C-linked 5- or 6-membered heterocyclic rings which may contain, nitrogen, oxygen or sulphur as heteroatoms, include, for example, furan, tetrahydrofuran, tetrahydrofuranone, -butyrolactone, -pyran, -pyran, dioxolane, tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole or pyrazolidine, whilst the heterocycle may be substituted as specified in the definitions.
xe2x80x9cxe2x95x90Oxe2x80x9d denotes an oxygen atom linked via a double bond.
The compounds according to the invention may be prepared as described in the prior art (Tenor et al., Chem. Ber. Vol. 97 (1964) p. 1373-1382), to which reference is hereby made (diagram 1). 
Diagram 1
The above method of synthesis already disclosed in the prior art can be used to prepare the compounds of general formula (I) according to the invention wherein the groups R2 or R3 and R4 or R6 denote hydrogen. In this case, the compounds of general formula (I) are tautomers, one tautomeric form of which is represented by formula (4) in diagram 1. The triazolopyrimidones referred to as compounds (1) in diagram 1 may be prepared by reacting cyanoacetic ester derivatives with suitably substituted 3-amino-1,2,4-triazoles as described by Tenor et al. in the introduction. The latter compounds can be obtained by methods known from the literature (J. Org. Chem. 1926, p. 1729; Org. Synthesis 26, p. 11; J. Chem. Soc. 1929, p. 816).
In order to obtain the compounds of general formula (I) wherein the groups R4 or R6 and R2 or R3 denote something other than hydrogen, the following procedure may be followed:
Before the reaction sequence described in the prior art and shown in diagram 1, the compounds (1) may be derivatised according to diagram 2. According to the invention, alkylation or benzylation is preferred as derivatisation. 
Diagram 2
The alkylation or benzylation to be carried out leads to the compounds (5). The isomeric alkylation products (5xe2x80x2) may possibly be obtained as well. Any mixtures of products (5) and (5xe2x80x2) obtained can be separated into the pure alkylation products (5) and (5xe2x80x2) using purification methods known to the skilled person, such as fractional crystallisation or chromatography.
The compounds (5) and (5xe2x80x2) are then subjected to the reaction sequence described by Tenor et al., as shown diagrammatically for the reaction of compounds (5) in diagram 3. 
Diagram 3
The procedure described above which can be carried out analogously to the prior art can be used to prepare the compounds of general formula (I) according to the invention wherein the groups R4 or R6 denote hydrogen. In this case, the compounds of general formula (I) are tautomers, one tautomeric form of which is represented by formula (8) in diagram 3.
Starting from the alkylation products (5xe2x80x2) the compounds (8xe2x80x2) may be obtained accordingly (diagram 4). 
Diagram 4
The method of synthesis described above which can be carried out analogously to the prior art can be used to prepare the compounds of general formula (I) according to the invention wherein the groups R4 or R6 denote hydrogen. In this case, the compounds of general formula (I) are tautomers, one tautomeric form of which is represented by formula (8xe2x80x2) in diagram 4.
Compounds (Ia) and (Ib) may be obtained by re-alkylation of the compounds (8) (Diagram 5). 
Diagram 5
Mostly the compounds (Ia) are isolated as the main products.
Analogously, the reaction of the derivatives (8xe2x80x2) leads to the compounds (Ic) and (Id) (Diagram 6). 
Diagram 6
Mostly the compounds (Ic) are isolated as the main products.
Depending on the substitution pattern, the compounds (Ia), (Ib), (Ic) or (Id) wherein the groups R1 to R6 may be defined as hereinbefore, can be further functionalised using methods known from the literature. These functionalisations comprise the processes familiar to the skilled person, namely oxidation, reduction, ether splitting, acylation, alkylation, etc. Moreover, the use of common protecting groups, especially common hydroxyl and amino protecting groups may be necessary. It is particularly preferable to use the p-methoxybenzyl group as a protecting group for a hydroxyl function, for example, in conjunction with the benzyl group as an amino protecting group.